Note pubs.acs.org/joc
Reacting Cyclopropenones with Arynes: Access to Spirocyclic Xanthene−Cyclopropene Motifs Jan Wallbaum, Peter G. Jones,† and Daniel B. Werz* Technische Universität Braunschweig, Institut für Organische Chemie, Hagenring 30, 38106 Braunschweig, Germany † Technische Universität Braunschweig, Institut für Anorganische Chemie, Hagenring 30, 38106 Braunschweig, Germany S Supporting Information *
ABSTRACT: A formal insertion of two aryne moieties into the carbon−oxygen double bond of cyclopropenone has been realized. Spirocyclic xanthene−cyclopropene scaffolds were obtained. Mechanistically, a sequence of a formal [2 + 2]cycloaddition followed by electrocyclic ring opening and a terminating [4 + 2]-type cycloaddition is postulated. The use of an electron-rich aryne precursor led to ring cleavage of the cyclopropene to afford an unprecedented xanthylium salt.
T
experiments have revealed that the nucleophilicity of the aldehyde oxygen is crucial for a successful reaction. The higher the electron density at this oxygen, easily modulable by electron-donating substituents at the phenyl moiety, the better the yields.3c Based upon these results, we were keen to test whether a ketone with a highly nucleophilic oxygen might also undergo a similar reaction.7 Therefore, we turned our attention to cyclopropenones. Because of their aromatic character and the resulting zwitterionic structure,8 they bear an extremely nucleophilic oxygen which has been used in various ringopening and ring-enlargement processes.8 In addition, the strained three-membered ring decreases the steric congestion around the carbon−oxygen double bond, thus facilitating the reaction. The anticipated transformation with two arynes in a similar way should give rise to spirocyclic xanthene−cyclopropene scaffolds (Scheme 1B). To test our notion, unsubstituted aryne precursor 1a and commercially available diphenylcyclopropenone (2a) were chosen. The use of CsF as fluoride source and acetonitrile as solvent at 30 °C turned out to be the best conditions, affording the desired product 3aa in 64% yield (Table 1). Methyl and halogen substituents at the phenyl group of the cyclopropenone were tolerated (3ab−af), even though in several cases both the temperature and the reaction time had to be increased. The yields decreased from the fluorine-containing 3ac to the iodinesubstituted 3af. We interpret this decrease as a result of the lower solubility with heavier halogens. Nitro substituents, even in the meta-position to the three-membered ring, completely shut down the reaction. This is probably a consequence of a less nucleophilic carbonyl oxygen of the cyclopropenone. Consistent with this observation is the observation that cyclopropenones 2g−j bearing electron-rich residues gave the best results of up to 80% yield for the methoxy substituent
he use of arynes as synthetically useful intermediates has flourished in the recent past.1 Formal [2 + 2]-cycloaddition reactions with carbon−carbon2 and carbon−heteroatom3,4 double bonds have found wide application. The enol form of several carbonyl and 1,3-dicarbonyl compounds reacts easily with arynes in a formal [2 + 2]-cycloaddition generating a benzocyclobutane derivative that affords, after immediate ringopening, the 1-acylated-2-alkylated benzene derivative.5 In contrast to easily enolizable carbonyl compounds, ketones such as acetone, benzophenone, or trifluoroacetophenone are only known to react with arynes in three-component reactions involving quinolines or phosphines.6 In these latter reactions, the nitrogen- or phosphorus-containing nucleophile attacks the highly electrophilic double bond of the aryne. The emerging nucleophilic adduct is intercepted by the ketone. In contrast to ketones, aldehydes have been demonstrated to react with arynes by insertion into the carbon−oxygen double bond (Scheme 1A).3c It was assumed that, after the initial formation of the four-membered benzoxete, a subsequent electrocyclic ring-opening takes place leading to a highly reactive o-quinone methide, which directly reacts with a second aryne to generate the tricyclic xanthene derivative. Mechanistic Scheme 1. Reaction of Arynes with Aldehydes and Anticipated Reaction with Cyclopropenones
Received: February 12, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
even less soluble bis(5-anthracenyl)cyclopropenone showed no reactivity. Two aryl moieties seem to be crucial for a successful reaction since cyclopropenones with one or two aliphatic moieties, such as methylphenylcyclopropenone or bis(tertbutyl)cyclopropenone, showed no conversion to 3al and 3am, irrespective of varying reaction times and temperatures, despite full consumption of the starting materials. Varying the aryne gave xanthenes 3ba/3b′a and 3ca in acceptable yields. Whereas the 3-methyl-substituted aryne precursor 1b resulted in a regioisomeric mixture with a slight preference for the sterically less congested isomer 3ba, the respective aryne precursor based on naphthalene afforded 3ca as a single isomer. To conduct the transformation with the fluorine-containing aryne precursor, an increased reaction temperature proved to be essential. Since different aryne precursors commonly require different reaction temperatures, we abstained from investigating whether different arynes might be used for mixed xanthene−cyclopropene scaffolds. Starting with a silylindanyl triflate, the electron-rich xanthene derivative 3ea is formed but decomposes during workup. This result can be explained by a closer look at the behavior of aryne precursors whose π system is even more electron-rich than in the case of indane. When the transformation was conducted with the bis(methoxy)-substituted precursor, the anticipated xanthene congener was formed. However, because of its high electron density, traces of acid lead to a cleavage of the highly strained cyclopropene moiety, resulting in xanthylium triflate 4.9 This cationic compound proved to be stable and could be purified by column chromatography. NOESY investigations confirmed the trans-arrangement of the Ph residues in 4. The same ring opening occurs in the case of 3ea, but the carbocation is not sufficiently stable and decomposes further. In general, slightly electron-rich xanthene cores as in the case of 3ba/3b′a and 3ca could be purified via column chromatography on neutral or basic alumina, whereas all other products are stable on silica gel.
Table 1. Scope of the 2-fold Aryne Insertion into the Carbon−Oxygen Bond of Cyclopropenones To Afford Xanthene−Cyclopropene Motifsa
Scheme 2. Transformation to Xanthylium Triflate 4
To prove the structure of the products unambiguously, we obtained single crystals of 3aa. The X-ray crystallographic analysis10,11 confirmed the generated xanthene−cyclopropene motif. The two π systems are mutually twisted by almost exactly 90°. The molecular structure (one of two independent molecules) is depicted in Figure 1. Although single crystals of the xanthylium triflate 4 were obtained, the structure, although qualitatively confirming the nature of 4, could not be refined satisfactorily because of severe disorder.
a
Reaction conditions: 1 (0.25 mmol), 2 (0.10 mmol), CsF (0.90 mmol), MeCN (4.0 mL), yield of isolated product based on 2. bRatio determined via 1H NMR.
(3ag). Naphthyl-substituted cyclopropenone 2k yielded only 17% of the desired product at 60 °C. The higher temperature was necessary because of its poor solubility in acetonitrile. The B
DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
In conclusion, we have developed the first direct formal [2 + 2]-cycloaddition of an aryne with a carbon−oxygen double bond of a ketone, followed by further reaction of the emerging o-quinone methide with a second aryne to give spirocyclic xanthene−cyclopropene motifs. With respect to the cyclopropenone, electron-withdrawing and -donating substituents at the aryl moiety were tolerated, furnishing the spirocyclic compounds in yields up to 80%. Variation of the aryne moiety is limited to slightly electron-rich, neutral, or electron-deficient aryne precursors. Electron-rich xanthene−cyclopropene cores evade the strained spirocyclic structure by formation of xanthylium salts. These investigations nicely complement previously studied reactions of arynes with other compounds of aromatic character such as tropone, furan, or anthracene.
Figure 1. Molecular structure (50% ellipsoid probability) of 3aa in the solid state (one of two independent molecules). The oxygen atom is shown in red.10,11
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Scheme 3 (top) depicts a plausible reaction mechanism assuming a nonradical pathway.12 As the initial step we expect
EXPERIMENTAL SECTION
General Experimental Methods. All solvents were distilled before use unless otherwise stated. Acetonitrile was purchased extra dry over molecular sieves. Air- and moisture-sensitive reactions were carried out in oven-dried or flame-dried glassware, septum-capped under atmospheric pressure of argon. Commercially available compounds were used without further purification unless otherwise stated. Proton (1H) and carbon (13C) NMR spectra were recorded on a 200, 300, 400, or 600 MHz instrument using residual signals from CHCl3, δ = 7.26 ppm and δ = 77.16 ppm, CH2Cl2, δ = 5.32 ppm and δ = 53.84 ppm, and CH3OH, δ = 3.31 ppm and δ = 49.00 ppm, as internal references for 1H and 13C chemical shifts, respectively. Additionally, tetramethylsilane (δ = 0.0 ppm) was added to the NMR samples. Structure elucidation was performed by a combination of NOESY, H,H−COSY, HSQC, and HMBC experiments. ESI-HRMS mass spectrometry was carried out on an FTICR instrument. IR spectra were measured on an ATR spectrometer. UV spectra were measured with a common photometer. General Procedure for the Synthesis of Xanthene−Cyclopropene Motifs. CsF (9.0 equiv) was placed in a round-bottom flask, which was heated for 2 h at 100 °C. After the CsF was cooled to ambient temperature, cyclopropenone (1.0 equiv), MeCN (25 μmol/ mL), and aryne precursor (2.5 equiv) were added, and the mixture was stirred at the given temperature and time. Solvent was evaporated, and the crude product was purified by column chromatography on silica gel (as otherwise stated) to afford the desired product. 2,3-Diphenylspiro[cyclopropane-1,9′-xanthen]-2-ene (3aa): 30 °C, 24 h; column chromatography, eluent: n-pentane/EtOAc = 200:1; white solid, 22.9 mg (64%); mp 159−160 °C dec; 1H NMR (600 MHz, CDCl3) δ 6.84 (ddd, J = 7.7, 7.0, 1.3 Hz, 2H), 6.90 (dd, J = 7.8, 1.6 Hz, 2H), 7.07 (dd, J = 8.1, 1.3 Hz, 2H), 7.09−7.14 (m, 2H), 7.29−7.36 (m, 2 H), 7.35−7.43 (m, 4H), 7.68 (dd, J = 8.3, 1.3 Hz, 4H); 13C NMR (150 MHz, CDCl3) δ 27.5, 107.4, 116.0, 122.9, 124.8, 126.2, 126.3, 126.9, 129.0, 129.1, 130.2, 154.3; IR (neat) ν̃ 3027, 1829, 1476, 1444, 1246, 1096 cm−1; UV/vis (MeCN) λmax (lg ε) 323 (4.32), 308 (4.51), 299 (4.45), 255 (4.60), 198 (4.85); HRMS (ESI) calcd for C27H19O [M + H]+ 359.1430, found 359.1431. 2,3-Di-p-tolylspiro[cyclopropane-1,9′-xanthen]-2-ene (3ab): 30 °C, 24 h; column chromatography, eluent n-pentane/EtOAc = 400:1; white solid, 24.0 mg (62%); mp 155−156 °C dec; 1H NMR (600 MHz, CDCl3) δ 2.37 (s, 6H), 6.83 (ddd, J = 7.7, 7.0, 1.3 Hz, 2H), 6.86−6.89 (m, 2H), 7.04−7.07 (m, 2 H), 7.10 (ddd, J = 8.2, 7.0, 1.7 Hz, 2H), 7.19−7.22 (m, 4H), 7.55−7.58 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 21.6, 27.2, 106.2, 115.9, 122.9, 123.4, 124.9, 126.6, 126.8, 129.7, 130.0, 139.2, 154.3; IR (neat) ν̃ 2990, 2917, 1832, 1510, 1476, 1251 cm−1; UV/vis (MeCN) λmax (lg ε) 331 (4.35), 314 (4.52), 303 (4.44), 239 (4.47), 227 (4.53), 200 (4.81); HRMS (ESI) calcd for C29H22O [M + H]+ 387.1743, found 387.1743. 2,3-Bis(4-fluorophenyl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3ac): 30 °C, 24 h; column chromatography, eluent n-pentane; white solid, 24.1 mg (61%); mp 152−153 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.86 (dd, J = 4.6, 1.3 Hz, 4H), 6.99−7.19 (m, 8H), 7.53−
Scheme 3. (Top) Proposed Reaction Mechanism Assuming a Nonradical Pathway; (Bottom) Potential Biradicalic Intermediates 5′ and 7′
an attack by the strongly nucleophilic oxygen of the cyclopropenone at the strained in-plane π system of the aryne, forming zwitterionic intermediate 5. This species can undergo a ring closure to the spirocyclic benzoxete derivative 6. Electrocyclic ring-opening affords reactive o-quinone methide 7, which reacts in a formal [4 + 2]-cycloaddition with a second aryne to generate the desired xanthene−cyclopropene motif 3. Recent theoretical studies on analogous Diels−Alder reactions (e.g. tropone and benzyne) have shown that also a biradicalic pathway might be possible. Therefore, putative biradicalic intermediates are depicted in Scheme 3 (bottom).12 All of our investigations to generalize this reaction to other nonenolizable ketones such as benzophenone, fluorenone, and dibenzosuberone showed no conversion; starting materials were recovered. These results demonstrate again the necessity of the extremely nucleophilic oxygen as it is found in cyclopropenone. C
DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry 7.73 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 27.5, 105.8 (d, 5J = 1.7 Hz), 116.1, 116.4 (d, 2J = 22.0 Hz), 122.3 (d, 4J = 2.7 Hz), 123.0, 124.6, 125.8, 127.2, 131.9 (d, 3J = 8.7 Hz), 154.3, 163.1 (d, 1J = 250.9 Hz); 19F NMR (375 MHz, CDCl3) δ −110.4; IR (neat) ν̃ 3044, 1822, 1597, 1503, 1447, 1216 cm−1; UV/vis (MeCN) λmax (lg ε) 321 (4.26), 306 (4.46), 297 (4.41), 224 (4.56), 198 (4.83); HRMS (ESI) calcd for C27H17F2O [M + H]+ 395.1242, found 395.1242. 2,3-Bis(4-chlorophenyl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3ad): 45 °C, 24 h; column chromatography, eluent n-pentane/EtOAc = 1000:1; yellow solid, 23.1 mg (54%); mp 163−164 °C dec; 1H NMR (300 MHz, CDCl3) δ 6.80−6.91 (m, 4H), 7.07 (ddd, J = 8.1, 1.2, 0.6 Hz, 2H), 7.11−7.18 (ddd, J = 8.1, 6.1, 2.6 Hz, 2H), 7.34−7.41 (m, 4H), 7.54−7.61 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 27.6, 106.9, 116.2, 123.0, 124.5, 124.6, 125.6, 127.3, 129.4, 131.3, 135.3, 154.3; IR (neat) ν̃ 3068, 1831, 1479, 1446, 1253, 1087 cm−1; UV/vis (MeCN) λmax (lg ε) 334 (4.32), 317 (4.46), 307 (4.40), 237 (4.37), 227 (4.45), 200 (4.75); HRMS (ESI) calcd for C27H17Cl2O [M + H]+ 427.0651, found 427.0652. 2,3-Bis(4-bromophenyl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3ae): 45 °C, 72 h; column chromatography, eluent n-pentane; yellow solid, 23.7 mg (46%); mp 170−171 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.78−6.92 (m, 4H), 7.07 (ddd, J = 8.1, 1.4, 0.7 Hz, 2H), 7.15 (ddd, J = 8.1, 5.7, 2.6 Hz, 2H), 7.45−7.58 (m, 8 H); 13C NMR (75 MHz, CDCl3) δ 27.5, 107.2, 116.2, 123.0, 123.7, 124.6, 124.9, 125.5, 127.3, 131.5, 132.4, 154.2; IR (neat) ν̃ 3065, 1829, 1480, 1446, 1252, 1096 cm−1; UV/vis (MeCN) λmax (lg ε) 337 (4.34), 320 (4.48), 309 (4.42), 238 (4.33), 222 (4.47), 200 (4.75); HRMS (ESI) calcd for C27H17Br2O [M + H]+ 514.9641, found 514.9640. 2,3-Bis(4-iodophenyl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3af): 60 °C, 24 h; column chromatography, eluent, n-pentane; yellow solid, 15.3 mg (25%); mp 169−170 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.77−6.92 (m, 4H), 7.06 (ddd, J = 8.2, 1.2, 0.6 Hz, 2H), 7.15 (ddd, J = 8.2, 5.9, 2.5 Hz, 2 H), 7.32−7.41 (m, 4H), 7.69−7.79 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 27.5, 95.6, 107.6, 116.2, 123.0, 124.6, 125.4, 125.5, 127.3, 131.6, 138.3, 154.2; IR (neat) ν̃ 2918, 1827, 1480, 1445, 1303, 1053 cm−1; UV/vis (MeCN) λmax (lg ε) 344 (4.36), 327 (4.49), 317 (4.38), 252 (4.17), 220 (4.42), 195 (4.74); HRMS (ESI) calcd for C27H17I2O [M + H]+ 610.9363, found 610.9363. 2,3-Bis(4-methoxyphenyl)spiro[cyclopropane-1,9′-xanthen]-2ene (3ag): 30 °C, 24 h; column chromatography, eluent n-pentane/ EtOAc = 40:1; white solid, 15.3 mg (25%); mp 153−154 °C dec; 1H NMR (200 MHz, CDCl3) δ 3.81 (s, 6H), 6.77−6.97 (m, 8H), 7.00− 7.16 (m, 4H), 7.53−7.63 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 27.5, 95.6, 107.6, 116.2, 123.0, 124.6, 125.4, 125.5, 127.3, 131.6, 138.3, 154.2; IR (neat) ν̃ 2956, 2823, 1824, 1601, 1445, 1209 cm−1; UV/vis (MeCN) λmax (lg ε) 343 (4.49), 324 (4.56), 308 (4.46), 246 (4.41), 200 (4.83); HRMS (ESI) calcd for C29H23O3 [M + H]+ 419.1642, found 419.1641. 2,3-Bis(2-methoxy-5-methylphenyl)spiro[cyclopropane-1,9′xanthen]-2-ene (3ah): 30 °C, 24 h; column chromatography, eluent n-pentane/EtOAc = 40:1; white solid, 34.8 mg (78%); mp 175−176 °C dec; 1H NMR (200 MHz, CDCl3) δ 2.26 (s, 6H), 3.70 (s, 6H), 6.77 (d, J = 8.4 Hz, 2H), 6.81−6.90 (m, 4H), 6.99−7.13 (m, 6H), 7.56 (d, J = 2.1 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 20.5, 27.3, 55.3, 103.4, 111.0, 115.3, 116.1, 122.4, 125.3, 126.1, 128.9, 129.7, 130.6, 132.7, 154.3, 157.1; IR (neat) ν̃ 2924, 2836, 1576, 1446, 1241, 973 cm−1; UV/vis (MeCN) λmax (lg ε) 363 (4.19), 347 (4.24), 299 (4.16), 239 (4.04), 205 (4.82); HRMS (ESI) calcd for C31H27O3 [M + H]+ 447.1955, found 447.1955. 2,3-Bis(2,4-dimethoxyphenyl)spiro[cyclopropane-1,9′-xanthen]2-ene (3ai): 30 °C, 24 h; column chromatography, eluent n-pentane/ EtOAc = 20:1; white solid, 31.0 mg (65%); mp 151−152 °C dec; 1H NMR (200 MHz, CDCl3) δ 3.72 (s, 6H), 3.80 (s, 6H), 6.40−6.51 (m, 4H), 6.79−6.88 (m, 4H), 6.99−7.09 (m, 4H), 7.63 (d, J = 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 27.0, 55.3, 55.4, 98.7, 100.9, 105.1, 109.7, 115.3, 122.4, 125.3, 125.9, 129.2, 132.8, 154.4, 160.1, 161.4; IR (neat) ν̃ 2935, 2836, 1603, 1446, 1252, 1207 cm−1; UV/vis (MeCN) λmax (lg ε) 364 (4.34), 347 (4.39), 305 (4.13), 242 (4.43),
204 (4.78); HRMS (ESI) calcd for C31H27O5 [M + H]+ 479.1853, found 479.1851. 2,3-Dimesitylspiro[cyclopropane-1,9′-xanthen]-2-ene (3aj): 30 °C, 24 h; column chromatography, eluent, n-pentane/EtOAc = 200:1; white solid, 35.1 mg, (79%); mp 90−91 °C dec; 1H NMR (400 MHz, CDCl3) δ 2.12 (s, 12H), 2.28 (s, 6H), 6.83−6.92 (m, 8H), 6.99 (dd, J = 8.1, 1.1 Hz, 2H), 7.09 (ddd, J = 8.1, 7.0, 1.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 21.1, 21.8, 32.0, 108.9, 115.8, 122.7, 124.7, 126.0, 126.8, 128.8, 129.4, 138.2, 139.3, 154.0; IR (neat) ν̃ 2916, 1804, 1609, 1476, 1446, 1205 cm−1; UV/vis (MeCN) λmax (lg ε) 388 (3.96), 289 (4.35), 245 (4.45), 189 (4.86); HRMS (ESI) calcd for C33H31O [M + H]+ 443.2369, found 443.2366. 2,3-Di(naphthalene-1-yl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3ak): 60 °C, 24 h; column chromatography, eluent n-pentane/ CH2Cl2 = 100:1; white solid, 7.9 mg (17%); mp 158−159 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.86 (ddd, J = 7.9, 5.9, 2.4 Hz, 2H), 7.03− 7.18 (m, 6H), 7.36 (ddd, J = 8.2, 6.8, 1.3 Hz, 2H), 7.42−7.56 (m, 4 H), 7.80 (dd, J = 7.1, 1.2 Hz, 2H), 7.80 (dd, J = 7.1, 1.2 Hz, 4H), 8.28 (ddd, J = 8.3, 0.7, 0.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 29.6, 107.3, 116.0, 122.9, 124.3, 125.0, 125.4, 126.0, 126.1, 126.5, 126.6, 127.0, 128.3, 129.1, 129.6, 132.1, 133.7, 154.0; IR (neat) ν̃ 2921, 2851, 1570, 1476, 1447, 1206 cm−1; UV/vis (MeCN) λmax (lg ε) 364 (4.08), 351 (4.08), 310 (4.07), 279 (3.83), 210 (4.91); HRMS (ESI) calcd for C35H22O [M]+ 458.1665, found 458.1662. 4′,5′-Dimethyl-2,3-diphenylspiro[cyclopropane-1,9′-xanthen]-2ene (3ba) and 1′,5′-dimethyl-2,3-diphenylspiro[cyclopropane-1,9′xanthen]-2-ene (3b′a): 30 °C, 24 h, basic alumina oxide column, eluent n-pentane/EtOAc = 200:1; white solid, 15.8 mg (41%), 2.5:1 mixture (ratio determined by 1H NMR); 1H NMR (600 MHz, CDCl3) δ 2.07 (s, 3H, Me-3b′a), 2.41 (s, 3H, Me-3b′a), 2.44 (s, 6H, 2 × Me-3ba), 6.65−6.76 (m, 8H), 6.94−7.03 (m, 4H), 7.32−7.36 (m, 4H), 7.37−7.45 (m, 8H), 7.62−7.77 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 15.5, 15.7, 21.8, 27.6, 28.3, 107.5, 111.6, 114.6, 121.8, 122.0, 122.2, 122.3, 123.9, 124.3, 125.0, 125.6, 126.1, 126.2, 126.7, 127.7, 128.1, 128.1, 128.7, 128.8, 128.8, 128.8, 129.7, 130.0, 136.0, 152.2, 152.4, 155.9; HRMS (ESI) calcd for C29H23O [M + H]+ 387.1743, found 387.1743. 2,3-Diphenylspiro[cyclopropane-1,7′-dibenzo[c,h]xanthen]-2ene (3ca): 30 °C, 24 h, basic alumina oxide column, eluent n-pentane/ EtOAc = 200:1; white solid, 25.6 mg (56%); mp 147−148 °C dec; 1H NMR (200 MHz, CD2Cl2) δ 7.05 (ddd, J = 8.5, 6.8, 1.6 Hz, 2H), 7.21 (ddd, J = 8.1, 6.8, 1.2 Hz, 2H), 7.35−7.56 (m, 8H), 7.68−7.79 (m, 4H), 7.88−7.98 (m, 4H), 8.38−8.46 (m, 2H); 13C NMR (150 MHz, CD2Cl2) δ 29.9, 116.7, 117.8, 120.1, 123.8, 125.1, 126.1, 129.0, 129.5, 129.6, 129.8, 129.8, 130.6, 131.7, 132.2, 154.6; IR (neat) ν̃ 3056, 1512, 1450, 1375, 1342, 1155 cm−1; UV/vis (MeCN) λmax (lg ε) 329 (4.21), 314 (4.27), 256 (4.50), 217 (4.71); HRMS (EI) calcd for C35H22O [M − H]+ 457.1587, found 457.1592. 2′,3′,6′,7′-Tetrafluoro-2,3-diphenylspiro[cyclopropane-1,9′xanthen]-2-ene (3da): 45 °C, 24 h; column chromatography, eluent n-pentane/EtOAc = 1000:1; white solid, 16.1 mg (37%); mp 159−160 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.64 (dd, J = 10.9, 8.5 Hz, 2H), 6.89 (dd, J = 10.7, 6.7 Hz, 2H), 7.35−7.54 (m, 6H), 7.56−7.73 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 26.5, 105.4 (d, 2J = 21.1 Hz), 106.5, 112.5 (d, 2J = 19.8 Hz), 121.5 (dd, 3,4J = 7.7, 3.8 Hz), 124.8, 129.1, 129.6, 129.9, 146.6 (dd, 1,2J = 243.4, 12.9 Hz), 148.7 (dd, 1,2 J = 247.6, 14.5 Hz), 149.1 (dd, 3,4J = 9.4, 2.4 Hz); 19F NMR (188 MHz, CDCl3) δ −139.1 (d, J = 22.0 Hz), −144.4 (d, J = 22.0 Hz); IR (neat) ν̃ 3052, 1821, 1623, 1496, 1447, 1154 cm−1; UV/vis (MeCN) λmax (lg ε) 321 (4.30), 306 (4.49), 296 (4.41), 224 (4.47), 198 (4.83); HRMS (ESI) calcd for C27H14F4O [M]+ 430.0975, found 430.0976. (E)-9-(1,2-Diphenylvinyl)-2,3,6,7-tetramethoxyxanthylium triflate (4): 35 °C, 24 h; column chromatography, eluent CH2Cl2/MeOH = 10:1; crystallization from n-hexane/CH2Cl2; dark red crystals 23.0 mg (37%); mp 127−128 °C dec; 1H NMR (300 MHz, CD3OD) δ 3.73 (s, 6H), 4.20 (s, 6H), 7.03−7.14 (m, 5 H), 7.28 (s, 2H), 7.34−7.47 (m, 6H), 7.78 (s, 2H), 7.96 (s, 1H); 13C NMR (75 MHz, CD3OD) δ 57.1, 58.7, 101.1, 106.2, 119.4, 128.0, 129.9, 130.0, 130.0, 130.1, 130.5, 134.4, 136.8, 137.3, 141.8, 152.4, 157.0, 163.0, 163.9; 19F NMR (188 MHz, CD3OD) δ −76.5; IR (neat) ν̃ 2941, 2835, 1627, 1493, 1261, D
DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry 1143 cm−1; UV/vis (MeCN) λmax (lg ε) 470 (4.65), 269 (4.65), 201 (4.62); HRMS (ESI) calcd for C31H27O5 [M − OTf]+ 479.1861, found 479.1853.
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Y.; Yoshikawa, Y.; Ohshita, J.; Takaki, K. Chem. Commun. 2011, 47, 8664−8666. (6) (a) Liu, P.; Lei, M.; Hu, L. Tetrahedron 2013, 69, 10405−10413. (b) Bhunia, A.; Porwal, D.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013, 15, 4620−4623. (c) Bhunia, A.; Roy, T.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2014, 16, 5132−5135. (7) Already in the 1960s, the reaction of tropone bearing a highly nucleophilic oxygen with arynes was investigated; however, Diels− Alder reactivity was observed: (a) Ciabattoni, J.; Crowley, J. E.; Kende, A. S. J. Am. Chem. Soc. 1967, 89, 2778−2779. (b) Miwa, T.; Kato, M.; Tamano, T. Tetrahedron Lett. 1969, 10, 1761−1764. (c) The same holds true for the reaction of the “antiaromatic” tetraphenylcyclopentadienone with aryne: Fieser, L. F.; Haddadin, M. J. Org. Synth. 1966, 46, 107−112. (8) (a) Werz, D. B.; Rominger, F.; Hyla-Kryspin, I.; Gleiter, R. J. Org. Chem. 2001, 66, 3416−3422. (b) Werz, D. B.; Gleiter, R.; Rominger, F. Eur. J. Org. Chem. 2003, 151−154. (c) Werz, D. B.; Gleiter, R.; Rominger, F. ARKIVOC 2005, 4, 102−109. (d) Schuster-Haberhauer, A.; Gleiter, R.; Körner, O.; Leskovar, A.; Werz, D. B.; Fischer, F. R.; Rominger, R. Organometallics 2008, 27, 1361−1366. (e) Werz, D. B.; Düfert, A. Org. Lett. 2008, 10, 5231−5234. (f) Körner, O.; Gleiter, R.; Rominger, F. Synthesis 2009, 19, 3259−3262. (g) Rivero, A. R.; Fernández, I.; de Arellano, C. R.; Sierra, M. A. J. Org. Chem. 2015, 80, 1207−1213. (9) Xanthylium salts are known and have been prepared by several methods: (a) Kamel, M.; Shoeb, H. Chem. Ber. 1966, 99, 1822−1829. (b) Oshima, T.; Nagai, T. Tetrahedron Lett. 1993, 34, 649−652. (c) Katritzky, A. R.; Czerney, P.; Levell, J. R. J. Org. Chem. 1997, 62, 8198−8200. (10) (a) CrysAlisPro; Agilent Technologies: Oxford, U.K., 2013. (b) . Sheldrick, G. M. SHELXL-97; University of Göttingen, Germany, 1997. (c) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112−122. (11) The CIF File has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-1042780 (3aa). (12) Yamabe, S.; Minato, T.; Watanabe, T.; Machiguchi, T. Theor. Chem. Acc. 2011, 130, 981−990.
ASSOCIATED CONTENT
* Supporting Information S
Copies of 1H and 13C NMR spectra of all new compounds. Xray crystallographic data of compound 3aa. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The research was supported by the German Research Foundation (DFG, Emmy Noether and Heisenberg Fellowship to D.B.W.) and by the Fonds der Chemischen Industrie (Dozentenstipendium to D.B.W.). We thank one of the reviewers, who pointed out that biradicalic intermediates also might play a role.
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REFERENCES
(1) For reviews on arynes: (a) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502−528. (b) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701−730. (c) Chen, Y.; Larock, R. C. in Modern Arylation Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim, 2009. (d) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140−3152. (e) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550−3577. (f) Gampe, C. M.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3766−3778. For a selection of recent examples: (g) Garve, L. K. B.; Werz, D. B. Org. Lett. 2015, 17, 596− 599. (h) Pawliczek, M.; Garve, L. K. B.; Werz, D. B. Org. Lett. 2015, DOI: 10.1021/acs.orglett.5b00494. (i) Garcı ́a-López, J.-A.; Cetin, M.; Greaney, M. F. Angew. Chem. Int. Ed. 2015, DOI: 10.1002/ anie.201410751. (2) (a) Stevens, R. V.; Bisacchi, G. S. J. Org. Chem. 1982, 47, 2393− 2396. (b) Matsumoto, T.; Yamaguchi, H.; Hamura, T.; Tanabe, M.; Kuriyama, Y.; Suzuki, K. Tetrahedron Lett. 2000, 41, 8383−8387. (c) Xie, C.; Zhang, Y. Org. Lett. 2007, 9, 781−784. (d) Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung, R. P. Org. Lett. 2009, 11, 3666−3669. (e) Bhojgude, S. S.; Thangaraj, M.; Suresh, E.; Biju, A. T. Org. Lett. 2014, 16, 3576−3579. (3) (a) Okuma, K.; Shiki, K.; Shioji, K. Chem. Lett. 1998, 27, 79−80. (b) Okuma, K.; Okada, A.; Koga, Y.; Yokomori, Y. J. Am. Chem. Soc. 2001, 123, 7166−7167. (c) Yoshida, H.; Watanabe, M.; Fukushima, H.; Ohshita, J.; Kunai, A. Org. Lett. 2004, 6, 4049−4051. (4) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2002, 41, 3247−3249. (b) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112−13113. (c) Yoshioka, E.; Kohtani, S.; Miyabe, H. Org. Lett. 2010, 12, 1956−1959. (d) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168−171. (e) Biswas, K.; Greaney, M. F. Org. Lett. 2011, 13, 4946−4949. (5) (a) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340−5341. (b) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem. Commun. 2005, 41, 3292−3294. (c) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2005, 46, 6729−6731. (d) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752−11753. (e) Huang, X.; Xue, J. J. Org. Chem. 2007, 72, 3695−3968. (f) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699−5713. (g) Yoshida, H.; Kishida, T.; Watanabe, M.; Ohshita, J. Chem. Commun. 2008, 44, 5963−5965. (h) Liu, Y.-L.; Liang, Y.; Pi, S.F.; Li, J.-H. J. Org. Chem. 2009, 74, 5691−5694. (i) Yoshida, H.; Ito, E
DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
Reacting Cyclopropenones with Arynes: Access to Spirocyclic Xanthene−Cyclopropene Motifs Jan Wallbaum, Peter G. Jones,† and Daniel B. Werz* Technische Universität Braunschweig, Institut für Organische Chemie, Hagenring 30, 38106 Braunschweig, Germany † Technische Universität Braunschweig, Institut für Anorganische Chemie, Hagenring 30, 38106 Braunschweig, Germany S Supporting Information *
ABSTRACT: A formal insertion of two aryne moieties into the carbon−oxygen double bond of cyclopropenone has been realized. Spirocyclic xanthene−cyclopropene scaffolds were obtained. Mechanistically, a sequence of a formal [2 + 2]cycloaddition followed by electrocyclic ring opening and a terminating [4 + 2]-type cycloaddition is postulated. The use of an electron-rich aryne precursor led to ring cleavage of the cyclopropene to afford an unprecedented xanthylium salt.
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experiments have revealed that the nucleophilicity of the aldehyde oxygen is crucial for a successful reaction. The higher the electron density at this oxygen, easily modulable by electron-donating substituents at the phenyl moiety, the better the yields.3c Based upon these results, we were keen to test whether a ketone with a highly nucleophilic oxygen might also undergo a similar reaction.7 Therefore, we turned our attention to cyclopropenones. Because of their aromatic character and the resulting zwitterionic structure,8 they bear an extremely nucleophilic oxygen which has been used in various ringopening and ring-enlargement processes.8 In addition, the strained three-membered ring decreases the steric congestion around the carbon−oxygen double bond, thus facilitating the reaction. The anticipated transformation with two arynes in a similar way should give rise to spirocyclic xanthene−cyclopropene scaffolds (Scheme 1B). To test our notion, unsubstituted aryne precursor 1a and commercially available diphenylcyclopropenone (2a) were chosen. The use of CsF as fluoride source and acetonitrile as solvent at 30 °C turned out to be the best conditions, affording the desired product 3aa in 64% yield (Table 1). Methyl and halogen substituents at the phenyl group of the cyclopropenone were tolerated (3ab−af), even though in several cases both the temperature and the reaction time had to be increased. The yields decreased from the fluorine-containing 3ac to the iodinesubstituted 3af. We interpret this decrease as a result of the lower solubility with heavier halogens. Nitro substituents, even in the meta-position to the three-membered ring, completely shut down the reaction. This is probably a consequence of a less nucleophilic carbonyl oxygen of the cyclopropenone. Consistent with this observation is the observation that cyclopropenones 2g−j bearing electron-rich residues gave the best results of up to 80% yield for the methoxy substituent
he use of arynes as synthetically useful intermediates has flourished in the recent past.1 Formal [2 + 2]-cycloaddition reactions with carbon−carbon2 and carbon−heteroatom3,4 double bonds have found wide application. The enol form of several carbonyl and 1,3-dicarbonyl compounds reacts easily with arynes in a formal [2 + 2]-cycloaddition generating a benzocyclobutane derivative that affords, after immediate ringopening, the 1-acylated-2-alkylated benzene derivative.5 In contrast to easily enolizable carbonyl compounds, ketones such as acetone, benzophenone, or trifluoroacetophenone are only known to react with arynes in three-component reactions involving quinolines or phosphines.6 In these latter reactions, the nitrogen- or phosphorus-containing nucleophile attacks the highly electrophilic double bond of the aryne. The emerging nucleophilic adduct is intercepted by the ketone. In contrast to ketones, aldehydes have been demonstrated to react with arynes by insertion into the carbon−oxygen double bond (Scheme 1A).3c It was assumed that, after the initial formation of the four-membered benzoxete, a subsequent electrocyclic ring-opening takes place leading to a highly reactive o-quinone methide, which directly reacts with a second aryne to generate the tricyclic xanthene derivative. Mechanistic Scheme 1. Reaction of Arynes with Aldehydes and Anticipated Reaction with Cyclopropenones
Received: February 12, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
even less soluble bis(5-anthracenyl)cyclopropenone showed no reactivity. Two aryl moieties seem to be crucial for a successful reaction since cyclopropenones with one or two aliphatic moieties, such as methylphenylcyclopropenone or bis(tertbutyl)cyclopropenone, showed no conversion to 3al and 3am, irrespective of varying reaction times and temperatures, despite full consumption of the starting materials. Varying the aryne gave xanthenes 3ba/3b′a and 3ca in acceptable yields. Whereas the 3-methyl-substituted aryne precursor 1b resulted in a regioisomeric mixture with a slight preference for the sterically less congested isomer 3ba, the respective aryne precursor based on naphthalene afforded 3ca as a single isomer. To conduct the transformation with the fluorine-containing aryne precursor, an increased reaction temperature proved to be essential. Since different aryne precursors commonly require different reaction temperatures, we abstained from investigating whether different arynes might be used for mixed xanthene−cyclopropene scaffolds. Starting with a silylindanyl triflate, the electron-rich xanthene derivative 3ea is formed but decomposes during workup. This result can be explained by a closer look at the behavior of aryne precursors whose π system is even more electron-rich than in the case of indane. When the transformation was conducted with the bis(methoxy)-substituted precursor, the anticipated xanthene congener was formed. However, because of its high electron density, traces of acid lead to a cleavage of the highly strained cyclopropene moiety, resulting in xanthylium triflate 4.9 This cationic compound proved to be stable and could be purified by column chromatography. NOESY investigations confirmed the trans-arrangement of the Ph residues in 4. The same ring opening occurs in the case of 3ea, but the carbocation is not sufficiently stable and decomposes further. In general, slightly electron-rich xanthene cores as in the case of 3ba/3b′a and 3ca could be purified via column chromatography on neutral or basic alumina, whereas all other products are stable on silica gel.
Table 1. Scope of the 2-fold Aryne Insertion into the Carbon−Oxygen Bond of Cyclopropenones To Afford Xanthene−Cyclopropene Motifsa
Scheme 2. Transformation to Xanthylium Triflate 4
To prove the structure of the products unambiguously, we obtained single crystals of 3aa. The X-ray crystallographic analysis10,11 confirmed the generated xanthene−cyclopropene motif. The two π systems are mutually twisted by almost exactly 90°. The molecular structure (one of two independent molecules) is depicted in Figure 1. Although single crystals of the xanthylium triflate 4 were obtained, the structure, although qualitatively confirming the nature of 4, could not be refined satisfactorily because of severe disorder.
a
Reaction conditions: 1 (0.25 mmol), 2 (0.10 mmol), CsF (0.90 mmol), MeCN (4.0 mL), yield of isolated product based on 2. bRatio determined via 1H NMR.
(3ag). Naphthyl-substituted cyclopropenone 2k yielded only 17% of the desired product at 60 °C. The higher temperature was necessary because of its poor solubility in acetonitrile. The B
DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
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In conclusion, we have developed the first direct formal [2 + 2]-cycloaddition of an aryne with a carbon−oxygen double bond of a ketone, followed by further reaction of the emerging o-quinone methide with a second aryne to give spirocyclic xanthene−cyclopropene motifs. With respect to the cyclopropenone, electron-withdrawing and -donating substituents at the aryl moiety were tolerated, furnishing the spirocyclic compounds in yields up to 80%. Variation of the aryne moiety is limited to slightly electron-rich, neutral, or electron-deficient aryne precursors. Electron-rich xanthene−cyclopropene cores evade the strained spirocyclic structure by formation of xanthylium salts. These investigations nicely complement previously studied reactions of arynes with other compounds of aromatic character such as tropone, furan, or anthracene.
Figure 1. Molecular structure (50% ellipsoid probability) of 3aa in the solid state (one of two independent molecules). The oxygen atom is shown in red.10,11
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Scheme 3 (top) depicts a plausible reaction mechanism assuming a nonradical pathway.12 As the initial step we expect
EXPERIMENTAL SECTION
General Experimental Methods. All solvents were distilled before use unless otherwise stated. Acetonitrile was purchased extra dry over molecular sieves. Air- and moisture-sensitive reactions were carried out in oven-dried or flame-dried glassware, septum-capped under atmospheric pressure of argon. Commercially available compounds were used without further purification unless otherwise stated. Proton (1H) and carbon (13C) NMR spectra were recorded on a 200, 300, 400, or 600 MHz instrument using residual signals from CHCl3, δ = 7.26 ppm and δ = 77.16 ppm, CH2Cl2, δ = 5.32 ppm and δ = 53.84 ppm, and CH3OH, δ = 3.31 ppm and δ = 49.00 ppm, as internal references for 1H and 13C chemical shifts, respectively. Additionally, tetramethylsilane (δ = 0.0 ppm) was added to the NMR samples. Structure elucidation was performed by a combination of NOESY, H,H−COSY, HSQC, and HMBC experiments. ESI-HRMS mass spectrometry was carried out on an FTICR instrument. IR spectra were measured on an ATR spectrometer. UV spectra were measured with a common photometer. General Procedure for the Synthesis of Xanthene−Cyclopropene Motifs. CsF (9.0 equiv) was placed in a round-bottom flask, which was heated for 2 h at 100 °C. After the CsF was cooled to ambient temperature, cyclopropenone (1.0 equiv), MeCN (25 μmol/ mL), and aryne precursor (2.5 equiv) were added, and the mixture was stirred at the given temperature and time. Solvent was evaporated, and the crude product was purified by column chromatography on silica gel (as otherwise stated) to afford the desired product. 2,3-Diphenylspiro[cyclopropane-1,9′-xanthen]-2-ene (3aa): 30 °C, 24 h; column chromatography, eluent: n-pentane/EtOAc = 200:1; white solid, 22.9 mg (64%); mp 159−160 °C dec; 1H NMR (600 MHz, CDCl3) δ 6.84 (ddd, J = 7.7, 7.0, 1.3 Hz, 2H), 6.90 (dd, J = 7.8, 1.6 Hz, 2H), 7.07 (dd, J = 8.1, 1.3 Hz, 2H), 7.09−7.14 (m, 2H), 7.29−7.36 (m, 2 H), 7.35−7.43 (m, 4H), 7.68 (dd, J = 8.3, 1.3 Hz, 4H); 13C NMR (150 MHz, CDCl3) δ 27.5, 107.4, 116.0, 122.9, 124.8, 126.2, 126.3, 126.9, 129.0, 129.1, 130.2, 154.3; IR (neat) ν̃ 3027, 1829, 1476, 1444, 1246, 1096 cm−1; UV/vis (MeCN) λmax (lg ε) 323 (4.32), 308 (4.51), 299 (4.45), 255 (4.60), 198 (4.85); HRMS (ESI) calcd for C27H19O [M + H]+ 359.1430, found 359.1431. 2,3-Di-p-tolylspiro[cyclopropane-1,9′-xanthen]-2-ene (3ab): 30 °C, 24 h; column chromatography, eluent n-pentane/EtOAc = 400:1; white solid, 24.0 mg (62%); mp 155−156 °C dec; 1H NMR (600 MHz, CDCl3) δ 2.37 (s, 6H), 6.83 (ddd, J = 7.7, 7.0, 1.3 Hz, 2H), 6.86−6.89 (m, 2H), 7.04−7.07 (m, 2 H), 7.10 (ddd, J = 8.2, 7.0, 1.7 Hz, 2H), 7.19−7.22 (m, 4H), 7.55−7.58 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 21.6, 27.2, 106.2, 115.9, 122.9, 123.4, 124.9, 126.6, 126.8, 129.7, 130.0, 139.2, 154.3; IR (neat) ν̃ 2990, 2917, 1832, 1510, 1476, 1251 cm−1; UV/vis (MeCN) λmax (lg ε) 331 (4.35), 314 (4.52), 303 (4.44), 239 (4.47), 227 (4.53), 200 (4.81); HRMS (ESI) calcd for C29H22O [M + H]+ 387.1743, found 387.1743. 2,3-Bis(4-fluorophenyl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3ac): 30 °C, 24 h; column chromatography, eluent n-pentane; white solid, 24.1 mg (61%); mp 152−153 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.86 (dd, J = 4.6, 1.3 Hz, 4H), 6.99−7.19 (m, 8H), 7.53−
Scheme 3. (Top) Proposed Reaction Mechanism Assuming a Nonradical Pathway; (Bottom) Potential Biradicalic Intermediates 5′ and 7′
an attack by the strongly nucleophilic oxygen of the cyclopropenone at the strained in-plane π system of the aryne, forming zwitterionic intermediate 5. This species can undergo a ring closure to the spirocyclic benzoxete derivative 6. Electrocyclic ring-opening affords reactive o-quinone methide 7, which reacts in a formal [4 + 2]-cycloaddition with a second aryne to generate the desired xanthene−cyclopropene motif 3. Recent theoretical studies on analogous Diels−Alder reactions (e.g. tropone and benzyne) have shown that also a biradicalic pathway might be possible. Therefore, putative biradicalic intermediates are depicted in Scheme 3 (bottom).12 All of our investigations to generalize this reaction to other nonenolizable ketones such as benzophenone, fluorenone, and dibenzosuberone showed no conversion; starting materials were recovered. These results demonstrate again the necessity of the extremely nucleophilic oxygen as it is found in cyclopropenone. C
DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry 7.73 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 27.5, 105.8 (d, 5J = 1.7 Hz), 116.1, 116.4 (d, 2J = 22.0 Hz), 122.3 (d, 4J = 2.7 Hz), 123.0, 124.6, 125.8, 127.2, 131.9 (d, 3J = 8.7 Hz), 154.3, 163.1 (d, 1J = 250.9 Hz); 19F NMR (375 MHz, CDCl3) δ −110.4; IR (neat) ν̃ 3044, 1822, 1597, 1503, 1447, 1216 cm−1; UV/vis (MeCN) λmax (lg ε) 321 (4.26), 306 (4.46), 297 (4.41), 224 (4.56), 198 (4.83); HRMS (ESI) calcd for C27H17F2O [M + H]+ 395.1242, found 395.1242. 2,3-Bis(4-chlorophenyl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3ad): 45 °C, 24 h; column chromatography, eluent n-pentane/EtOAc = 1000:1; yellow solid, 23.1 mg (54%); mp 163−164 °C dec; 1H NMR (300 MHz, CDCl3) δ 6.80−6.91 (m, 4H), 7.07 (ddd, J = 8.1, 1.2, 0.6 Hz, 2H), 7.11−7.18 (ddd, J = 8.1, 6.1, 2.6 Hz, 2H), 7.34−7.41 (m, 4H), 7.54−7.61 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 27.6, 106.9, 116.2, 123.0, 124.5, 124.6, 125.6, 127.3, 129.4, 131.3, 135.3, 154.3; IR (neat) ν̃ 3068, 1831, 1479, 1446, 1253, 1087 cm−1; UV/vis (MeCN) λmax (lg ε) 334 (4.32), 317 (4.46), 307 (4.40), 237 (4.37), 227 (4.45), 200 (4.75); HRMS (ESI) calcd for C27H17Cl2O [M + H]+ 427.0651, found 427.0652. 2,3-Bis(4-bromophenyl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3ae): 45 °C, 72 h; column chromatography, eluent n-pentane; yellow solid, 23.7 mg (46%); mp 170−171 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.78−6.92 (m, 4H), 7.07 (ddd, J = 8.1, 1.4, 0.7 Hz, 2H), 7.15 (ddd, J = 8.1, 5.7, 2.6 Hz, 2H), 7.45−7.58 (m, 8 H); 13C NMR (75 MHz, CDCl3) δ 27.5, 107.2, 116.2, 123.0, 123.7, 124.6, 124.9, 125.5, 127.3, 131.5, 132.4, 154.2; IR (neat) ν̃ 3065, 1829, 1480, 1446, 1252, 1096 cm−1; UV/vis (MeCN) λmax (lg ε) 337 (4.34), 320 (4.48), 309 (4.42), 238 (4.33), 222 (4.47), 200 (4.75); HRMS (ESI) calcd for C27H17Br2O [M + H]+ 514.9641, found 514.9640. 2,3-Bis(4-iodophenyl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3af): 60 °C, 24 h; column chromatography, eluent, n-pentane; yellow solid, 15.3 mg (25%); mp 169−170 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.77−6.92 (m, 4H), 7.06 (ddd, J = 8.2, 1.2, 0.6 Hz, 2H), 7.15 (ddd, J = 8.2, 5.9, 2.5 Hz, 2 H), 7.32−7.41 (m, 4H), 7.69−7.79 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 27.5, 95.6, 107.6, 116.2, 123.0, 124.6, 125.4, 125.5, 127.3, 131.6, 138.3, 154.2; IR (neat) ν̃ 2918, 1827, 1480, 1445, 1303, 1053 cm−1; UV/vis (MeCN) λmax (lg ε) 344 (4.36), 327 (4.49), 317 (4.38), 252 (4.17), 220 (4.42), 195 (4.74); HRMS (ESI) calcd for C27H17I2O [M + H]+ 610.9363, found 610.9363. 2,3-Bis(4-methoxyphenyl)spiro[cyclopropane-1,9′-xanthen]-2ene (3ag): 30 °C, 24 h; column chromatography, eluent n-pentane/ EtOAc = 40:1; white solid, 15.3 mg (25%); mp 153−154 °C dec; 1H NMR (200 MHz, CDCl3) δ 3.81 (s, 6H), 6.77−6.97 (m, 8H), 7.00− 7.16 (m, 4H), 7.53−7.63 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 27.5, 95.6, 107.6, 116.2, 123.0, 124.6, 125.4, 125.5, 127.3, 131.6, 138.3, 154.2; IR (neat) ν̃ 2956, 2823, 1824, 1601, 1445, 1209 cm−1; UV/vis (MeCN) λmax (lg ε) 343 (4.49), 324 (4.56), 308 (4.46), 246 (4.41), 200 (4.83); HRMS (ESI) calcd for C29H23O3 [M + H]+ 419.1642, found 419.1641. 2,3-Bis(2-methoxy-5-methylphenyl)spiro[cyclopropane-1,9′xanthen]-2-ene (3ah): 30 °C, 24 h; column chromatography, eluent n-pentane/EtOAc = 40:1; white solid, 34.8 mg (78%); mp 175−176 °C dec; 1H NMR (200 MHz, CDCl3) δ 2.26 (s, 6H), 3.70 (s, 6H), 6.77 (d, J = 8.4 Hz, 2H), 6.81−6.90 (m, 4H), 6.99−7.13 (m, 6H), 7.56 (d, J = 2.1 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 20.5, 27.3, 55.3, 103.4, 111.0, 115.3, 116.1, 122.4, 125.3, 126.1, 128.9, 129.7, 130.6, 132.7, 154.3, 157.1; IR (neat) ν̃ 2924, 2836, 1576, 1446, 1241, 973 cm−1; UV/vis (MeCN) λmax (lg ε) 363 (4.19), 347 (4.24), 299 (4.16), 239 (4.04), 205 (4.82); HRMS (ESI) calcd for C31H27O3 [M + H]+ 447.1955, found 447.1955. 2,3-Bis(2,4-dimethoxyphenyl)spiro[cyclopropane-1,9′-xanthen]2-ene (3ai): 30 °C, 24 h; column chromatography, eluent n-pentane/ EtOAc = 20:1; white solid, 31.0 mg (65%); mp 151−152 °C dec; 1H NMR (200 MHz, CDCl3) δ 3.72 (s, 6H), 3.80 (s, 6H), 6.40−6.51 (m, 4H), 6.79−6.88 (m, 4H), 6.99−7.09 (m, 4H), 7.63 (d, J = 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 27.0, 55.3, 55.4, 98.7, 100.9, 105.1, 109.7, 115.3, 122.4, 125.3, 125.9, 129.2, 132.8, 154.4, 160.1, 161.4; IR (neat) ν̃ 2935, 2836, 1603, 1446, 1252, 1207 cm−1; UV/vis (MeCN) λmax (lg ε) 364 (4.34), 347 (4.39), 305 (4.13), 242 (4.43),
204 (4.78); HRMS (ESI) calcd for C31H27O5 [M + H]+ 479.1853, found 479.1851. 2,3-Dimesitylspiro[cyclopropane-1,9′-xanthen]-2-ene (3aj): 30 °C, 24 h; column chromatography, eluent, n-pentane/EtOAc = 200:1; white solid, 35.1 mg, (79%); mp 90−91 °C dec; 1H NMR (400 MHz, CDCl3) δ 2.12 (s, 12H), 2.28 (s, 6H), 6.83−6.92 (m, 8H), 6.99 (dd, J = 8.1, 1.1 Hz, 2H), 7.09 (ddd, J = 8.1, 7.0, 1.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 21.1, 21.8, 32.0, 108.9, 115.8, 122.7, 124.7, 126.0, 126.8, 128.8, 129.4, 138.2, 139.3, 154.0; IR (neat) ν̃ 2916, 1804, 1609, 1476, 1446, 1205 cm−1; UV/vis (MeCN) λmax (lg ε) 388 (3.96), 289 (4.35), 245 (4.45), 189 (4.86); HRMS (ESI) calcd for C33H31O [M + H]+ 443.2369, found 443.2366. 2,3-Di(naphthalene-1-yl)spiro[cyclopropane-1,9′-xanthen]-2-ene (3ak): 60 °C, 24 h; column chromatography, eluent n-pentane/ CH2Cl2 = 100:1; white solid, 7.9 mg (17%); mp 158−159 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.86 (ddd, J = 7.9, 5.9, 2.4 Hz, 2H), 7.03− 7.18 (m, 6H), 7.36 (ddd, J = 8.2, 6.8, 1.3 Hz, 2H), 7.42−7.56 (m, 4 H), 7.80 (dd, J = 7.1, 1.2 Hz, 2H), 7.80 (dd, J = 7.1, 1.2 Hz, 4H), 8.28 (ddd, J = 8.3, 0.7, 0.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 29.6, 107.3, 116.0, 122.9, 124.3, 125.0, 125.4, 126.0, 126.1, 126.5, 126.6, 127.0, 128.3, 129.1, 129.6, 132.1, 133.7, 154.0; IR (neat) ν̃ 2921, 2851, 1570, 1476, 1447, 1206 cm−1; UV/vis (MeCN) λmax (lg ε) 364 (4.08), 351 (4.08), 310 (4.07), 279 (3.83), 210 (4.91); HRMS (ESI) calcd for C35H22O [M]+ 458.1665, found 458.1662. 4′,5′-Dimethyl-2,3-diphenylspiro[cyclopropane-1,9′-xanthen]-2ene (3ba) and 1′,5′-dimethyl-2,3-diphenylspiro[cyclopropane-1,9′xanthen]-2-ene (3b′a): 30 °C, 24 h, basic alumina oxide column, eluent n-pentane/EtOAc = 200:1; white solid, 15.8 mg (41%), 2.5:1 mixture (ratio determined by 1H NMR); 1H NMR (600 MHz, CDCl3) δ 2.07 (s, 3H, Me-3b′a), 2.41 (s, 3H, Me-3b′a), 2.44 (s, 6H, 2 × Me-3ba), 6.65−6.76 (m, 8H), 6.94−7.03 (m, 4H), 7.32−7.36 (m, 4H), 7.37−7.45 (m, 8H), 7.62−7.77 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 15.5, 15.7, 21.8, 27.6, 28.3, 107.5, 111.6, 114.6, 121.8, 122.0, 122.2, 122.3, 123.9, 124.3, 125.0, 125.6, 126.1, 126.2, 126.7, 127.7, 128.1, 128.1, 128.7, 128.8, 128.8, 128.8, 129.7, 130.0, 136.0, 152.2, 152.4, 155.9; HRMS (ESI) calcd for C29H23O [M + H]+ 387.1743, found 387.1743. 2,3-Diphenylspiro[cyclopropane-1,7′-dibenzo[c,h]xanthen]-2ene (3ca): 30 °C, 24 h, basic alumina oxide column, eluent n-pentane/ EtOAc = 200:1; white solid, 25.6 mg (56%); mp 147−148 °C dec; 1H NMR (200 MHz, CD2Cl2) δ 7.05 (ddd, J = 8.5, 6.8, 1.6 Hz, 2H), 7.21 (ddd, J = 8.1, 6.8, 1.2 Hz, 2H), 7.35−7.56 (m, 8H), 7.68−7.79 (m, 4H), 7.88−7.98 (m, 4H), 8.38−8.46 (m, 2H); 13C NMR (150 MHz, CD2Cl2) δ 29.9, 116.7, 117.8, 120.1, 123.8, 125.1, 126.1, 129.0, 129.5, 129.6, 129.8, 129.8, 130.6, 131.7, 132.2, 154.6; IR (neat) ν̃ 3056, 1512, 1450, 1375, 1342, 1155 cm−1; UV/vis (MeCN) λmax (lg ε) 329 (4.21), 314 (4.27), 256 (4.50), 217 (4.71); HRMS (EI) calcd for C35H22O [M − H]+ 457.1587, found 457.1592. 2′,3′,6′,7′-Tetrafluoro-2,3-diphenylspiro[cyclopropane-1,9′xanthen]-2-ene (3da): 45 °C, 24 h; column chromatography, eluent n-pentane/EtOAc = 1000:1; white solid, 16.1 mg (37%); mp 159−160 °C dec; 1H NMR (200 MHz, CDCl3) δ 6.64 (dd, J = 10.9, 8.5 Hz, 2H), 6.89 (dd, J = 10.7, 6.7 Hz, 2H), 7.35−7.54 (m, 6H), 7.56−7.73 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 26.5, 105.4 (d, 2J = 21.1 Hz), 106.5, 112.5 (d, 2J = 19.8 Hz), 121.5 (dd, 3,4J = 7.7, 3.8 Hz), 124.8, 129.1, 129.6, 129.9, 146.6 (dd, 1,2J = 243.4, 12.9 Hz), 148.7 (dd, 1,2 J = 247.6, 14.5 Hz), 149.1 (dd, 3,4J = 9.4, 2.4 Hz); 19F NMR (188 MHz, CDCl3) δ −139.1 (d, J = 22.0 Hz), −144.4 (d, J = 22.0 Hz); IR (neat) ν̃ 3052, 1821, 1623, 1496, 1447, 1154 cm−1; UV/vis (MeCN) λmax (lg ε) 321 (4.30), 306 (4.49), 296 (4.41), 224 (4.47), 198 (4.83); HRMS (ESI) calcd for C27H14F4O [M]+ 430.0975, found 430.0976. (E)-9-(1,2-Diphenylvinyl)-2,3,6,7-tetramethoxyxanthylium triflate (4): 35 °C, 24 h; column chromatography, eluent CH2Cl2/MeOH = 10:1; crystallization from n-hexane/CH2Cl2; dark red crystals 23.0 mg (37%); mp 127−128 °C dec; 1H NMR (300 MHz, CD3OD) δ 3.73 (s, 6H), 4.20 (s, 6H), 7.03−7.14 (m, 5 H), 7.28 (s, 2H), 7.34−7.47 (m, 6H), 7.78 (s, 2H), 7.96 (s, 1H); 13C NMR (75 MHz, CD3OD) δ 57.1, 58.7, 101.1, 106.2, 119.4, 128.0, 129.9, 130.0, 130.0, 130.1, 130.5, 134.4, 136.8, 137.3, 141.8, 152.4, 157.0, 163.0, 163.9; 19F NMR (188 MHz, CD3OD) δ −76.5; IR (neat) ν̃ 2941, 2835, 1627, 1493, 1261, D
DOI: 10.1021/acs.joc.5b00330 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry 1143 cm−1; UV/vis (MeCN) λmax (lg ε) 470 (4.65), 269 (4.65), 201 (4.62); HRMS (ESI) calcd for C31H27O5 [M − OTf]+ 479.1861, found 479.1853.
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Y.; Yoshikawa, Y.; Ohshita, J.; Takaki, K. Chem. Commun. 2011, 47, 8664−8666. (6) (a) Liu, P.; Lei, M.; Hu, L. Tetrahedron 2013, 69, 10405−10413. (b) Bhunia, A.; Porwal, D.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013, 15, 4620−4623. (c) Bhunia, A.; Roy, T.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2014, 16, 5132−5135. (7) Already in the 1960s, the reaction of tropone bearing a highly nucleophilic oxygen with arynes was investigated; however, Diels− Alder reactivity was observed: (a) Ciabattoni, J.; Crowley, J. E.; Kende, A. S. J. Am. Chem. Soc. 1967, 89, 2778−2779. (b) Miwa, T.; Kato, M.; Tamano, T. Tetrahedron Lett. 1969, 10, 1761−1764. (c) The same holds true for the reaction of the “antiaromatic” tetraphenylcyclopentadienone with aryne: Fieser, L. F.; Haddadin, M. J. Org. Synth. 1966, 46, 107−112. (8) (a) Werz, D. B.; Rominger, F.; Hyla-Kryspin, I.; Gleiter, R. J. Org. Chem. 2001, 66, 3416−3422. (b) Werz, D. B.; Gleiter, R.; Rominger, F. Eur. J. Org. Chem. 2003, 151−154. (c) Werz, D. B.; Gleiter, R.; Rominger, F. ARKIVOC 2005, 4, 102−109. (d) Schuster-Haberhauer, A.; Gleiter, R.; Körner, O.; Leskovar, A.; Werz, D. B.; Fischer, F. R.; Rominger, R. Organometallics 2008, 27, 1361−1366. (e) Werz, D. B.; Düfert, A. Org. Lett. 2008, 10, 5231−5234. (f) Körner, O.; Gleiter, R.; Rominger, F. Synthesis 2009, 19, 3259−3262. (g) Rivero, A. R.; Fernández, I.; de Arellano, C. R.; Sierra, M. A. J. Org. Chem. 2015, 80, 1207−1213. (9) Xanthylium salts are known and have been prepared by several methods: (a) Kamel, M.; Shoeb, H. Chem. Ber. 1966, 99, 1822−1829. (b) Oshima, T.; Nagai, T. Tetrahedron Lett. 1993, 34, 649−652. (c) Katritzky, A. R.; Czerney, P.; Levell, J. R. J. Org. Chem. 1997, 62, 8198−8200. (10) (a) CrysAlisPro; Agilent Technologies: Oxford, U.K., 2013. (b) . Sheldrick, G. M. SHELXL-97; University of Göttingen, Germany, 1997. (c) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112−122. (11) The CIF File has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-1042780 (3aa). (12) Yamabe, S.; Minato, T.; Watanabe, T.; Machiguchi, T. Theor. Chem. Acc. 2011, 130, 981−990.
ASSOCIATED CONTENT
* Supporting Information S
Copies of 1H and 13C NMR spectra of all new compounds. Xray crystallographic data of compound 3aa. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The research was supported by the German Research Foundation (DFG, Emmy Noether and Heisenberg Fellowship to D.B.W.) and by the Fonds der Chemischen Industrie (Dozentenstipendium to D.B.W.). We thank one of the reviewers, who pointed out that biradicalic intermediates also might play a role.
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REFERENCES
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